Systems and methods for plasma collection

ABSTRACT

A plasmapheresis system and a method for operating a plasmapheresis system are provided by which a volume of plasma product (i.e., anticoagulated plasma) so that that the targeted volume of pure plasma in the plasma product is determined based on donor-specific characteristics. In particular, the targeted amount of pure plasma to be collected is based on the weight, or the weight and the height, of the donor. The targeted volume of pure plasma to be collected, TVP, may be a multiple of the donors weight. Alternatively, TVP may be a multiple of the donor&#39;s total blood volume, TBV, with the TBV of the donor being determined based on the donor&#39;s weight and height. A target volume for the plasma product to be collected, TVPP, is established, and separation of whole blood into a plasma component and a second component continues until the volume of plasma product in a collection container equals TVPP.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation of U.S. Ser. No. 17/861,437,filed Jul. 11, 2022, which is a Continuation of U.S. Ser. No.17/306,099, filed May 3, 2021, which claims the benefit of U.S.63/140,534, filed Jan. 22, 2021 and which is a Continuation-in Part ofU.S. Ser. No. 16/739,441, filed Jan. 10, 2020; which is a Continuationof PCT/US2019/033318, filed May 21, 2019, which claims the benefit ofeach of U.S. 62/846,400, filed May 10, 2019, U.S. 62/752,480, filed Oct.30, 2018, and U.S. 62/674,144, filed May 21, 2018, all of the aboveapplications being incorporated by reference herein in their entireties.

BACKGROUND

The present application relates to systems and methods for performingplasmapheresis and, more particularly, to plasmapheresis systems andmethods in which the volume of pure plasma that may be collected from aparticular donor is optimized.

Plasmapheresis is an apheresis procedure in which whole blood iswithdrawn from a donor, plasma is separated from other cellular bloodcomponents (red blood cells, platelets, and leukocytes) and retained,and the cellular blood components are returned to the donor. Theseparation of the plasma from the cellular components is typicallyaccomplished in an automated procedure by centrifugation or membranefiltration.

In automated plasmapheresis, whole blood is drawn from the donor, mixedat a specified ratio with anticoagulant, and then separated into plasma,red blood cells, and other cellular components. Once a target volume ofanticoagulated plasma (or “plasma product”) has been collected, asdetermined by a weigh scale associated with a plasma collectioncontainer, the withdrawal of whole blood from the donor ceases, and thered blood cells and other cellular components are returned to the donor.Often, the plasma product is collected in multiple collection andreinfusion cycles, until the total target volume of anticoagulatedplasma has been collected. The anticoagulated plasma may be used forlater transfusion or further manufacturing.

Plasma that is collected to serve as a source material (“source plasma”)for further manufacturing is collected from multiple donors and combinedor pooled together for this purpose. The FDA issued guidelines forregistered blood collection centers as to the volume of plasma that maybe collected as source plasma during plasmapheresis in order to improvethe consistency of procedures for manufacturing source plasma, and tominimize the opportunity for staff error. (FDA Memo: “VolumeLimits-Automated Collection of Source Plasma (11/4/92)”).

The FDA Memo set forth a simplified plasma volume nomogram, in which thevolume (or weight) of pure (or raw) plasma that may be collected from aparticular donor is limited to ensure donor safety and comfort. Morespecifically, the FDA nomogram limits the volume (or weight) of plasmabased on the weight of the donor, and establishes the volume ofanticoagulant that may be added to a 1:16 ratio of anticoagulant toanticoagulated blood, or 0.06 parts anticoagulant to 1 partanticoagulated blood, to arrive at a maximum collection volume for thetotal of the plasma plus the anticoagulant for a particular donor.

The simplified nomogram set forth in the FDA Memo has been thepredominant method for determining plasma product collection volumesused by blood collection centers. Therefore, the plasmapheresis devicesused at such centers are commonly programmed to collect a specifiedvolume/weight of anticoagulated plasma (assuming a known density) inaccordance with the maximum collection volume permitted by the FDAnomogram, with the anticoagulant being added to the whole blood at a1:16 or 0.06 ratio.

One simplification made in the FDA nomogram is to exclude theconsideration of donor hematocrit in determining the targeted collectionvolume for the plasma product. However, the relative proportions of pureplasma and anticoagulant in the plasma product depends on the donorblood hematocrit and the ratio at which the anticoagulant is combinedwith the donor's whole blood. As a consequence, higher hematocrit donorsreach the maximum collection volume set forth in the FDA nomogram beforereaching the maximum pure plasma volume that may be safely collectedfrom the donor. This represents an inefficiency for the plasmacollection center, in that the volume of pure plasma that is collectedis less than the maximum amount possible.

Further, the amount of pure plasma that may be safely collected from adonor can depend on factors in addition to the donor's weight andhematocrit that affect the donor's total blood volume, such as thedonor's height.

Because the source plasma from multiple donors is combined, it isimportant to maximize the pure plasma volume that may be collected fromeach individual donor, as even small gains in volume collected from eachindividual donor, when added together, result in a meaningful increasein the total volume of the pooled plasma. If a plasmapheresis devicewere to be able to better target the pure plasma volume, more plasmaproteins could be collected from each donor, improving the overallefficiency of the plasma collection center. Accordingly, by way of thepresent disclosure, systems and methods for optimizing the volume ofplasma collected are provided which are consistent with donor safety andcomfort.

SUMMARY

In a first aspect of the present disclosure, a system is provided forcollecting plasma from a donor in which the system comprises: avenipuncture needle for withdrawing whole blood from the donor, a bloodseparator for separating the whole blood into a plasma product and asecond blood component comprising red blood cells, a donor line coupledto the venipuncture needle for introducing whole blood from the donor tothe blood separator, a first pump for controlling flow through the donorline, an anticoagulant line coupled to an anticoagulant source forcombining anticoagulant with the whole blood, and a second pump forcontrolling flow through the anticoagulant line.

A touchscreen is provided for receiving input from an operator to acontroller programmed to control operation of the system. The controlleris configured to determine a target volume of plasma product to becollected (TVPP), either based on the weight of the donor and the donorhematocrit, or based on the weight and height of the donor and the donorhematocrit, to control the system to operate a draw and return cycle towithdraw whole blood from the donor, to add anticoagulant to the wholeblood at a pre-determined ratio (ACR), to separate the anticoagulatedwhole blood into the plasma product and the second component and toreturn the second component to the donor, and to stop withdrawing wholeblood from the donor and initiate a final return of the second bloodcomponent when a measured volume of plasma product in a plasmacollection container reaches the target volume for plasma product.

In a second aspect, the controller is programmed to calculate i) atarget volume of pure plasma to be collected (TVP) based on the weightof the donor and ii) a percentage of anticoagulant in the target volumeof plasma product to be collected (% AC_(TVPP)) based on thepre-determined anticoagulant ratio, ACR, and the donor hematocrit,wherein the TVPP=TVP/(1−% AC_(TVPP)).

In a third aspect, the controller is programmed to calculate a totalblood volume of the donor (TBV) based on the weight and height of thedonor, a target volume of pure plasma to be collected (TVP) as apercentage of the TBV, and a percentage of anticoagulant in the targetvolume of plasma product to be collected (% AC_(TVPP)) based on thepre-determined anticoagulant ratio (ACR) and the donor hematocrit,wherein the TVPP=TVP/(1−% AC_(TVPP)).

In a fourth aspect, the controller is programmed to calculate the totalblood volume of the donor (TBV) based on the weight and height of thedonor to calculate a body mass index for the donor (BMI) such thatTBV=70/(sqrtBMI/22) (Lemmens equation).

In a fifth aspect, the controller is programmed to calculate the totalblood volume of the donor (TBV) based on the weight (Wt), height (Ht)and sex (Male or Female) of the donor such thatTBV=(0.3669*Ht³)+(0.03219*Wt)+0.6041 for Males andTBV=(0.3561*Ht³)+(0.03308*Wt)+0.1833 for Females, where Ht is in metersand Wt is in kilograms (Nadler's formula).

In a sixth aspect, methods are provided for performing plasmapheresis tocollect a volume of plasma product (i.e., anticoagulated plasma, VPP) sothat that the targeted volume of pure plasma (TVP) in the plasma productis determined based on donor-specific characteristics, consistent withthe donor's safety and comfort. In particular, the targeted volume ofpure plasma to be collected, TVP, is based on the weight, or the weightand the height, of the donor.

In a seventh aspect, the targeted volume of pure plasma to be collected,TVP, may be a multiple of the donor's weight. Alternatively, TVP may bea multiple of the donor's total blood volume, TBV, with the TBV of thedonor being determined based on the donor's weight and height, usingwell established methodology, such as the Lemmens equation or Nadler'sformula.

A target volume for the plasma product to be collected, TVPP, isestablished based on the target volume/weight of pure plasma and thepercentage of anticoagulant, AC, in the plasma product, % AC_(TVPP),such that TVPP=TVP/(1−% AC_(TVPP)), wherein % AC_(TVPP) is based on anAC ratio, ACR, and the hematocrit of the donor.

Once the TVPP is determined, the plasmapheresis procedure is commenced,with whole blood being drawn from the donor, mixed at a specified ratiowith anticoagulant, and then separated into plasma, red blood cells, andother cellular components. Once the TVPP has been collected, asdetermined by, e.g., a weigh scale associated with a plasma collectioncontainer, the withdrawal of whole blood from the donor ceases, and thered blood cells and other cellular components are returned to the donor.

In a seventh aspect, in determining the target amount for the plasmaproduct to be collected, the hematocrit of the donor may be determinedprior to the collection phase of each cycle, either by calculation or onthe basis of a signal from a sensor or the like that is indicative ofthe donor's hematocrit. Further, the amount of plasma product in theplasma collection container may be determined by: e.g., a weigh scaleassociated with the plasma collection container or an optical sensorthat directly measures the volume.

In other aspects, a method is provided for operating a plasmapheresissystem to collect a plasma product volume that comprises the maximumallowable volume/weight of raw plasma in accordance with the limits setforth in the FDA nomogram based on the weight of the donor.

In order to collect the maximum volume/weight of raw plasma permitted bythe FDA nomogram, a modified nomogram is provided that utilizes thedonor's hematocrit to calculate a target volume/weight for a plasmaproduct having the maximum volume of raw plasma permitted by the FDAnomogram. A calculated volume/weight of raw plasma is compared to themaximum volume/weight for the raw plasma permitted by the FDA nomogram.If the calculated volume/weight of raw plasma is less than the maximumpermitted volume/weight, the volume/weight of the plasma product to becollected is adjusted upward from the maximum volume/weight permitted bythe FDA nomogram for the plasma product by an amount equal to thedifference plus the additional amount of anticoagulant that is added toprocess the additional volume/weight of plasma.

Thus, with the knowledge of the donor's hematocrit and the instrument'sAC ratio, the volume of additional raw plasma that may be safelycollected from the donor consistent with the limits set forth in the FDAnomogram is determined, and then the total volume/weight of plasmaproduct to be collected based on the weight of the donor set forth inthe FDA nomogram is adjusted accordingly.

Typically, plasmapheresis procedures involve sequential cycles ofalternating phases, one in which whole blood is withdrawn from the donorand the plasma separated and collected, and the other in which theseparated red blood cells and any other non-RBC cellular components arereturned to the donor. The donor's hematocrit will change during thecourse of the plasmapheresis procedure, thus affecting the amount ofanticoagulant in the plasma product collected from one cycle to thenext.

Consequently, in the first aspect of the disclosure, before thecommencement of the subsequent extraction/separation phase, a newhematocrit value for the donor is determined, and the targetvolume/weight of plasma product for the procedure is recalculated beforethe commencement of each extraction/separation phase to ensure that themaximum amount of raw plasma permitted by the FDA nomogram is collected.

In another aspect, a further method for collecting a volume of plasmaduring an apheresis procedure is provided. The steps of the methodcomprise: determining a total whole blood volume V_(b) for the donor;determining a volume of raw plasma (V_(RP)) that may be collected fromthe donor based on V_(b); determining a target volume of plasma product(V_(PP)) to be collected, wherein VF is equal to the volume of rawplasma (V_(RP)) to be collected plus a volume of anticoagulant (V_(AC))that is added to the V_(RP) during the apheresis procedure, such thatV_(PP)=V_(RP)*K, where K=(ACR*(1−Hct/100)+1)/(ACR*(1−Hct/100)), based onan anticoagulant ratio (ACR, defined as the ratio of donor blood volumeto anticoagulant volume for donor blood having no anticoagulant)established for the procedure and a Hct of the donor; withdrawing wholeblood from the donor; adding anticoagulant to the whole blood in anamount consistent with the ACR; separating plasma product from the wholeblood; and transferring the plasma product to a collection containeruntil the volume of plasma product in the collection container reachesV_(PP). Because the plasmapheresis procedure comprises multipleextraction/separation and return phases, the V_(PP) for the procedure isrecalculated before each extraction/separation phase is commenced, basedon a value for the hematocrit of the donor determined prior to the startof each draw phase, and the target volume for the plasma productadjusted accordingly. Alternatively. V_(RP) may be determined based on acalculated value for the donor's total plasma volume, based on V_(b) andthe donor's hematocrit.

In another aspect, a method for determining a volume of plasma product(V_(PP)) that may be collected during an apheresis procedure isprovided, wherein V_(PP) is equal to a volume of raw plasma (V_(RP))that may be collected plus a volume of anticoagulant (V_(AC)) that isadded to the V_(RP) during the apheresis procedure. The steps of themethod comprise: determining a weight (W_(kg)) and sex (M or F) of thedonor, determining a hematocrit (Hct) for the donor; determining thevolume of raw plasma (V_(RP)) that may be collected based on the weight(W_(kg)) and sex (M or F) of the donor; determining a ratio K betweenthe VP and the V_(RP), such that K=V_(PP)/V_(RP), based on ananticoagulant ratio (ACR) and the Hct of the donor; determining V_(PP),such that V_(PP)=V_(RP)*K. Further,K=(ACR*(1−Hct/100)+1)/(ACR*(1−Hct/100)). After V_(PP) is determined,whole blood is withdrawn from the donor; anticoagulant is added to thewhole blood in an amount consistent with the ACR; plasma product isseparated from the whole blood; and plasma product is transferred to acollection container. After a desired amount of whole blood has beenwithdrawn from the donor, the red blood cells are returned to the donor.Then, the Hct of the donor and V_(PP) are determined prior to each drawphase.

In a related aspect, the draw and separation steps are repeated untilthe volume of plasma product in the collection container reaches V_(PP).

In a related aspect, the donor's hematocrit subsequent to the firstcollection phase may be calculated by a volume balance, assuming thatthe donor's quantity of red blood cells is the same at the start of eachdraw cycle, while the total volume of blood decreases from one cycle tothe next in an amount equal to the amount of raw plasma collected.Alternatively, the donor's hematocrit at the start of each draw cyclecan be measured by an optical or other sensor.

In a further aspect, the volume of raw plasma that may be collected froma particular donor may be determined by any one of several differentmeans. Such means include, e.g., the FDA nomogram, taking into accountonly the donor's weight; a modified FDA nomogram, further taking intoaccount the donor's hematocrit, and taking a fraction of a total bloodvolume or total plasma volume calculated for a particular donor. Thetotal blood volume or total plasma volume may be determined using, forexample, Nadler's equations, Gilcher's Rule of Five, tables provided bythe International Council for Standardization in Haematology (ICSH), orany other generally accepted method using the donor's height, weight,sex, and age, consistent with the safety and comfort of the donor.

In another aspect, an automated system for separating plasma from wholeblood is provided that comprises a reusable hardware component and adisposable kit. The disposable kit further comprises i) a separator forseparating whole blood into a plasma fraction and a concentrated cellfraction, the separator having an input having a blood line integrallyconnected thereto for transporting whole blood from a donor to theseparator, a plasma output port integrally connected to a plasmacollection container by a plasma line, and a concentrated cell outletport integrally connected to a reservoir for receipt of concentratedcells prior to reinfusion to the donor; ii) a donor line terminating ina venipuncture needle for transporting whole blood from a donor to theblood line, iii) an anticoagulant line integrally connected to the bloodline and configured to be connected to a source of anticoagulant fortransporting anticoagulant to the donor line, and iv) a reinfusion linefor transporting concentrated cells from the reservoir to the donorline.

The reusable hardware component further comprises i) a first peristalticpump for delivering anticoagulant at a controlled rate into the bloodline during a collection phase, ii) a second pump for deliveringanticoagulated whole blood to the separator during the collection phaseand for returning concentrated cellular components during a reinfusionphase, iii) a third pump for delivering concentrated cellular componentsfrom the separator to the reservoir during the collection phase, iv) aclamp associated with each of the blood line, plasma line, andreinfusion line, v) a weigh scale for weighing each of the plasmacollection container, the reservoir and the source of anticoagulant, andvi) a programmable controller comprising a touch screen for receivinginput from an operator, the programmable controller configured toreceive a signal from each of the weigh scales and to automaticallyoperate the first, second and third pumps and the clamps to separatewhole blood into a plasma fraction and a concentrated cell fractionduring the collection phase and to return concentrated cells to thedonor during the reinfusion stage. The programmable controller isfurther configured to determine a target amount for the plasma productto be collected in the plasma collection container in accordance withany of the methods described herein, and to terminate the collectionphase upon receiving a signal that the amount of plasma product in theplasma collection container equal to the target amount of the plasmaproduct determined by the controller. In determining the target amountfor the plasma product to be collected, the controller may be configuredto calculate the hematocrit of the donor prior to the collection phaseof each cycle. Alternatively, or additionally, the controller mayreceive a signal from a sensor or the like that is indicative of thedonor's hematocrit. Further, the amount of plasma product in the plasmacollection container may be determined by, e.g., the weigh scaleassociated with the plasma collection container or an optical sensorthat directly measures the volume.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an exemplary plasmapheresis instrumentsuitable for use in the system and method of the present application.

FIG. 2 is a perspective view of a spinning membrane separator of thetype incorporated in a disposable set, with portions broken away to showdetail, usable with the plasmapheresis system of FIG. 1 .

FIG. 3 is a perspective view of the front panel of the plasmapheresissystem of FIG. 1 showing the components of the disposable set that aremounted thereto.

FIG. 4 is a schematic view showing operation of the plasmapheresissystem in the collection phase.

FIG. 5 is a schematic view showing operation of the plasmapheresissystem in the reinfusion phase.

FIGS. 6 a and 6 b are flow charts showing the steps of methods used inthe present application for collecting a target volume of pure plasma.

FIG. 7 is a table that shows the volume of pure plasma, based on donorhematocrit, that is contained within a plasma product volume limit setby the FDA nomogram using a 1:16 ratio of anticoagulant to whole blood.

FIG. 8 is a table that shows the volume of “unclaimed” pure plasma inthe plasma product based on the difference between the values set forthin FIG. 7 and the maximum volume of pure plasma that may be collectedbased on the FDA nomogram.

FIG. 9 is a table that shows the volume of plasma product that may becollected from a donor, based on the donor's weight and hematocrit, thatresults in the maximum permissible volume of pure plasma permitted bythe FDA nomogram.

FIG. 10 is a table showing the inputs to a programmable controller forperforming a hypothetical plasmapheresis procedure in accordance withthe method of the present application.

FIGS. 11 a, 11 b comprise a table, broken into two parts illustratinghow the donor's hematocrit increases over the course of a hypotheticalplasmapheresis procedure based on the inputs from the table of FIG. 10 ,and resulting in an increase in the total collection volume of plasmaproduct necessary to collect the target volume of pure plasma.

FIG. 12 is a graph illustrating IgG dilution during plasmapheresis.

DETAILED DESCRIPTION

A more detailed description of the systems and methods in accordancewith the present disclosure is set forth below. It should be understoodthat the description below of specific devices and methods is intendedto be exemplary, and not exhaustive of all possible variations orapplications. Thus, the scope of the disclosure is not intended to belimiting, and should be understood to encompass variations orembodiments that would occur to persons of ordinary skill. Variousaspects of the system and method are described in greater detail in US2020/0147289, which is incorporated herein by reference.

In the context of the present application, plasmapheresis is performedon an automated system comprising a hardware component, generallydesignated 10, and a disposable set, generally designated 12, to collectplasma to be processed as source plasma. With reference to FIGS. 1-5 ,and as described in greater detail below, the disposable set 12 consistsof an integrally connected separator, containers, and tubing totransport blood and solutions within a sterile fluid pathway.

The separator 14, best seen in FIG. 2 , has a spinning membrane filter16 mounted to a rotor 18 for rotation within a case 20 to separate bloodinto components. A detailed description of a spinning membrane separatormay be found in U.S. Pat. No. 5,194,145 to Schoendorfer, which isincorporated herein by reference. As can be appreciated, in a differentsystem, separation of the whole blood may be accomplished bycentrifugation. See, e.g., U.S. Pat. No. 5,360,542 to Williamson et al.

During plasmapheresis, anticoagulated whole blood enters the separator14 through a whole blood input port 22. The plasma is separated by thespinning membrane filter and then passes out of a plasma output port 24,through a plasma line 26, and into a plasma collection container 28.Concentrated cells are pumped out of a concentrated cell output port 30into a reservoir 32, where the cells remain until reinfusion to thedonor.

The disposable set 12 also includes tubing lines for introducing wholeblood from the donor into the system during collection and returningconcentrated cells to the donor during reinfusion (donor line 34, whichterminates in the venipuncture needle 36), and for transportinganticoagulated whole blood to the separator (blood line 38),concentrated cells into the reservoir (cell line 40), concentrated cellsfrom the reservoir to the donor line (reinfusion line 42), plasma intothe plasma collection container (plasma line 44), saline (saline line46), and anticoagulant (AC line 48).

The hardware component 10 includes a programmable controller 50 andtouch screen 52 with a graphical user interface (“GUI”) through whichthe operator controls the procedure. For example, the GUI permits entryof any of a donor ID, donor sex, donor height, donor weight, donor age,donor hematocrit/hemoglobin; a target saline infusion volume (if asaline protocol is selected), and a target plasma volume. The touchscreen 52 also enables the operator to gather status information andhandle error conditions.

Three peristaltic pumps are located on the front panel of the hardwarecomponent 10, including an AC pump 54, a blood pump 56, and a cell pump58. The AC pump 54 delivers anticoagulant solution (AC) at a controlledrate into the blood line 38 as whole blood enters the set from thedonor. The blood pump 56 delivers anticoagulated whole blood to theseparator during the collection phase of the procedure and returnsconcentrated cellular components and, if desired, replacement fluid tothe donor during the reinfusion phase of the procedure. The cell pump 58delivers concentrated cellular components from the separator 14 to areservoir during the collection phase.

The front panel also includes four clamps into which tubings from thedisposable set 12 are installed, including a reinfusion clamp 60, ablood clamp 62, a saline clamp 64, and a plasma clamp 66. The reinfusionclamp 60 closes to block the reinfusion line (42) during the collectionphase (FIG. 5 ) and is open during the reinfusion phase (FIG. 5 ) toallow the blood pump to reinfuse the concentrated cellular componentsfrom the reservoir 32 to the donor. The blood clamp 62 opens during thecollection phase to allow anticoagulated whole blood to be pumped to theseparator 14 and closes during the reinfusion phase to block the bloodline 38. The saline clamp 64 closes to block the saline line 46 duringthe collection phase and during reinfusion of the separated cellularcomponents. If saline is to be used as a replacement fluid, the salineclamp 64 opens during the reinfusion phase. The plasma clamp 66 opensduring the collection phase to allow plasma to flow into the plasmacollection container 28 and closes during the reinfusion phase.

The hardware component 10 includes three weigh scales to monitor thecurrent plasma collection volume (scale 68), the AC solution volume(scale 70), and the concentrated cellular content volume (scale 72). Thesystem also includes various sensors and detectors, including a venouspressure sensor 74, a separator pressure sensor 76, optical blooddetectors 78, and an air detector 80.

The donor is connected to the system throughout the procedure. Asillustrated, the disposable set 12 includes a single venipuncture needle36, through which whole blood is drawn from the donor in a collectionphase (FIG. 4 ) and concentrated cells are returned to the donor in areinfusion stage (FIG. 5 ). As noted above, the plasmapheresis proceduremay comprise a plurality of cycles each having a collection/separationphase followed by a return or reinfusion phase. During the collectionphase, the whole blood is separated into plasma and concentrated cells.The disposable set includes a plasma collection container 28 for receiptof the separated plasma and a reservoir 32 for receipt of theconcentrated cells. During the reinfusion phase, the concentrated cellsfrom the reservoir 32 are reinfused to the donor through thevenipuncture needle 36. Plasmapheresis performed with a singlevenipuncture needle 36 may involve multiple cycles of collection andreinfusion.

Returning to FIG. 4 , during the collection phase, anticoagulantsolution (AC) is pumped at a controlled rate and mixed with whole bloodas it enters the disposable set 12. The anticoagulated blood is pumpedto the separator 14, where plasma is separated from the cellularcomponents and directed to the plasma collection container 28.

The cellular components are pumped from the separator 14 to thereservoir 32. The collection phase stops when the reservoir 32 reachesan expected volume of concentrated cells or if the target plasmacollection volume has been achieved.

Then, the reinfusion phase begins. With reference to FIG. 5 , during thereinfusion phase, the blood pump 56 reverses direction and pumps theconcentrated cells from the reservoir 32 back to the donor through theapheresis needle 36. If a saline protocol was selected, by which salineis returned to the donor as a replacement fluid for the collectedplasma, the final reinfusion phase is followed by saline infusion.

The automated plasma collection device is configured to collect avolume/weight of anticoagulated plasma (i.e., the plasma product) havingthe maximum volume/weight of raw plasma permitted for the donor underthe limits set forth in the FDA nomogram. In order to maximize thevolume of raw plasma comprising the plasma product, the device isprogrammed with a nomogram that accounts for the donor's hematocrit.With the knowledge of the donor's hematocrit and the instrument's ACratio, the total volume/weight of plasma product to be collected can bedetermined such that the plasma product includes the maximumvolume/weight of raw plasma fraction that may be collected from a donor,consistent with the limits for total volume/weight of raw plasma setforth in the FDA nomogram. By having the computations programmed intothe controller, the likelihood of operator error is diminished incomparison to the off-line calculation of the collection volume that isthen entered into the instrument.

During plasmapheresis, when anticoagulant is mixed with whole blood asit is drawn from the donor, the anticoagulant is evenly distributedwithin the pure/raw plasma in the blood. However, the amount of pure/rawplasma in the whole blood is dependent on the hematocrit (Hct) of thewhole blood. The following relationships are established:

Volume of RBC=Volume of Whole Blood*Hct/100.  [1]

Volume of Pure/Raw Plasma=Volume of Whole Blood*(1−Hct/100).  [2]

When anticoagulant is mixed with the whole blood, it may be metered atan AC Ratio (ACR) of 16 parts of whole blood to 1 part of AC, or at 1part of whole blood to 0.06 parts of AC.

ACR=Volume of Whole Blood/Volume of Anticoagulant (the donor bloodhaving no anticoagulant).  [3]

(This yields a slightly different result from the FDA nomogram, which,as noted above, standardizes the volume of anticoagulant that may beadded to a 1:16 ratio of anticoagulant to anticoagulated blood, or 0.06parts anticoagulant to 1 part anticoagulated blood.)

Volume of Anticoagulated Blood=Volume of Anticoagulant+Volume of WholeBlood.   [4]

Combining equations gives:

Volume of Pure/Raw Plasma=ACR*Volume of Anticoagulant*(1−Hct/100).  [5]

Since the red cells are given back to the donor:

Volume collected Plasma Product=Volume of Pure/Raw Plasma+Volume ofAnticoagulant.  [6]

Equations [5] and [6] can be combined to calculate the amount ofanticoagulant in a given amount of collected plasma:

Volume of Anticoagulant=Volume of collected PlasmaProduct/(1+ACR*(1−Hct/100)).  [7]

Further

Volume of collected Plasma Product=Volume of Pure/Raw Plasma*K, whereK=(ACR*(1−Hct/100)+1)/(ACR*(1−Hct/100)).  [8]

In view of the relationships expressed in the equations above, thevolume of pure/raw plasma contained within the volume of plasma productpermitted under the FDA nomogram can be determined based upon thehematocrit of the donor. The results of such calculations are set forthin FIG. 7 , which shows the volume of pure/raw plasma based on donorhematocrit that is contained within a plasma product volume limit set bythe FDA nomogram.

As can be appreciated with reference to FIG. 7 , for donors weighingfrom 110 to 149 lbs. (for whom the maximum plasma product volume per theFDA nomogram is 690 mL), if the donor has a hematocrit of 42 or greater,the volume of raw plasma collected is less than the 625 mL permitted bythe FDA nomogram. The situation is similar for donors having a weight of150 to 174 lbs. (for whom the maximum plasma collection volume per theFDA nomogram is 825 mL) and for donors having a weight of 175 lbs. andup (for whom the maximum plasma collection volume per the FDA nomogramis 880 ml) when the donor's hematocrit is 40 or greater.

The table set forth in FIG. 8 presents the volume of “unclaimed” rawplasma in the plasma product based the difference between the values setforth in FIG. 7 and the maximum volume of pure/raw plasma that may becollected based on the FDA nomogram. Thus, as shown in the table setforth in FIG. 9 , the plasma product collected from any particular donormay be adjusted from that set forth in the FDA nomogram by an amountcorresponding to the amount of “unclaimed” pure/raw plasma set forth inFIG. 8 plus the amount of anticoagulant needed to process the additionalvolume.

Alternatively, the volume of plasma product to be collected may becalculated by first determining a weight and hematocrit (Hct) for thedonor; determining the volume of raw plasma (V_(RP)) that may becollected based on the weight of the donor (W_(kg)); determining a ratioK between the V_(PP) and the V_(RP), such that K=V_(PP)/V_(RP), based onan anticoagulant ratio (ACR; 1:16 or 0.06:1, per the FDA nomogram) andthe Hct of the donor; and determining V_(PP), such that V_(PP)=V_(RP)*K.Further, K=(ACR*(1−Hct/100)+1)/(ACR*(1−Hct/100)).

In a further alternative, the volume of plasma product that is to becollected (V_(PP)) may be calculated by first determining the weight(W_(kg)) and hematocrit (Hct) of the donor; determining the volume ofraw plasma (V_(RP)) that may be collected based on the weight of thedonor (W_(kg)); determining the volume of anticoagulant to be added(V_(AC)) based on the anticoagulant ratio (ACR; 1:16 or 0.06:1, per theFDA nomogram) and the hematocrit of the donor such thatV_(AC)=V_(RP)*(ACR*(1−Hct/100)); and determining the collection volumesuch that V_(PP)=V_(RP)+V_(AC).

In keeping with one aspect of the disclosure, the automated plasmacollection device is configured to collect a volume/weight of plasmaproduct (pure plasma+anticoagulant) having a volume/weight of pureplasma permitted for the donor as determined by either of the twomethods set forth in greater detail below.

With reference to FIG. 6 a , a first method (70) for collecting a targetvolume of plasma product, TVPP, is illustrated. In the method, thetarget volume of plasma product (TVPP) is determined by firstcalculating a target volume of pure plasma to be collected (TVP) basedon the weight of the donor (Step 72) and then determining a percentageof anticoagulant in the target volume of plasma product to be collected(% AC_(TVPP)) based on the pre-determined anticoagulant ratio (ACR) andthe hematocrit of the donor, wherein the TVPP=TVP/(1−% AC_(TVPP)) (Step74). In this method no intervening calculation is required of either atotal blood volume or a total plasma volume of the donor prior todetermining the target collection volume of plasma for the donor,though, in alternate embodiments, such calculations may be included.

Various methods may be used for determining a target volume of pureplasma that may be collected directly from the weight of the donor. Forexample, the weight of the donor may be multiplied by an establishedconstant “K₁” (such as 10 mL/kg). Alternatively, the weight of the donormay be segregated into weight categories or ranges (e.g., at least threecategories, at least six categories, etc.), with a fixed volumeestablished for each category (as in the FDA nomogram discussed above,in which the ranges of donor weight are divided into three categories).

The anticoagulant ratio, ACR, may be defined in one of two differentways. In a first way, ACR is the ratio of the amount of whole blood tothe amount of anticoagulant (ACR=WB/AC). In a second way, ACR is theratio of volume of whole blood plus the volume of anticoagulant to thevolume of anticoagulant (ACR=(WB+AC)/AC). If ACR=WB/AC, then the percentof anticoagulant in the target volume of plasma product, % AC_(TVPP), isdetermined according to the following equation: %AC_(TVPP)=1/(1+ACR(1−Hct)), with ACR and Hct being expressed aspercentages. If ACR=(WB+AC)/AC), then the percent of anticoagulant inthe target volume of plasma product, % AC_(TVPP), is determinedaccording to the following equation: % AC_(TVPP)=1/(1+(ACR−1)(1−Hct)).The ACR may be expressed as either a ratio or a percentage, and may varyfrom 7:1 to 20:1, or from about 5% to 14%. An exemplary ACR is 16:1, or6.25%.

Returning to FIG. 6 a , once the TVPP has been determined, as describedabove, whole blood is withdrawn from the donor (Step 76) and combinedwith anticoagulant based on a predetermined ratio, ACR (Step 78).Anticoagulated whole blood is then introduced into separator 14, whereit is separated into plasma and concentrated (red blood) cells (Step80). Plasma product (pure plasma and anticoagulant) is collected inplasma collection container 28 (Step 82) while separated red blood cellsare collected in reservoir 32. As the plasma product is being collected,the volume of plasma product, V_(PP), (pure plasma and anticoagulant) inthe plasma container is determined (Step 84). When the V_(PP) equals theTarget volume of plasma product (TVPP), withdrawal of whole blood ceasesand any remaining blood components (such as red blood cells) arereturned to the donor (Step 86).

With reference to FIG. 6 b , a second method (90) for collecting atarget volume of plasma product. TVPP, is illustrated. In this method,the target volume of plasma product, TPPV, is determined by firstcalculating a total blood volume of the donor (TBV) based on the weightand height of the donor (Step 92), calculating a target volume of pureplasma product to be collected, TVP, as a percentage of the TBV (Step94), and calculating a percentage of anticoagulant in the target volumeof plasma product to be collected (% AC_(TVPP)) based on thepre-determined anticoagulant ratio (ACR) and the hematocrit of the donor(Step 96), and calculating TVPP wherein TVPP=TVP/(1−% AC_(TVPP)) (Step98). The % AC_(TVPP) may be determined as described above in connectionwith the first method. In this method no calculation of a total plasmavolume of the donor is required to determine the target collectionvolume of plasma for the donor.

A donor's plasma volume may be estimated based on the donor's totalblood volume, and a volume of plasma that may be harvested consistentwith donor safety and comfort may be based on this estimation. Methodsutilizing donor parameters are commonly used estimate a donor's totalblood volume. The donor's total blood volume may be determined using oneor more of Lemmens equation (that uses the donor's body mass index todetermine a total blood volume), Nadler's equations (that take intoaccount the height, sex and weight of the donor), Gilcher's Rule of Five(that takes into account sex, weight and morphology (obese, thin, normalor muscular), or the standards of the International Counsel forStandardization in Haematology (“ICSH) as set forth in Br. J. Haem.1995, 89:748-56) (that consider the height, weight, age, and sex of thedonor). Any other methodology for determining donor's total blood volumemay also be used. In another embodiment, a plurality of suchmethodologies may be used and the average, mean, or a weighted averageof the methodologies may be taken as the donor's total blood volume. Forexample, once the donor's total blood volume is determined, the donor'splasma volume may be estimated by multiplying the total blood volume bya constant “K₂”, where or K₂ equals (1−Hct of the donor).

From an analysis of demographic, examination, and laboratory data fromthe 2015-2016 National Health and Nutrition Examination Survey, in whichsex, age, height, weight, pregnancy data and hematocrit were extracted,presented in Pearson et al., Interpretation of measured red cell massand plasma volume in adults: Expert Panel on Radionuclides of theInternational Council for Standardization in Haematology, British J.Haematology, 89: 748-756 (1995), (upon which the ICSH recommendedformulae were derived), it has been determined that for donors havingcertain characteristics (namely low weight females with highhematocrits), up to 36% of the available plasma may be collected whilestaying within current regulations. Plasmapheresis procedures with suchdonors have been carried out routinely without adverse reactions, andthus are considered safe. This suggests that up to 36% of a donor'savailable plasma can be safely collected in a plasmapheresis procedure.

Given that only negative deviations of a donor's true blood volume froma predicted/calculated total blood volume present a potential risk, afurther adjustment downward of the harvestable volume of plasma may beappropriate. Based on a consideration of the deviation between thecalculated blood volume as determined in Pearson et al., cited above.

Thus, the total blood volume of the donor (TBV) may be calculated basedon the weight (WA) and height (Ht) of the donor to calculate a body massindex for the donor (BMI) such that TBV=70/sqrt(BMI/22), whereBMI=Wt/Ht², and where Ht is in meters and Wt is in kilograms (Lemmensequation). See, “Estimating Blood Volume in Obese and Morbidly ObesePatients,” Lemmens et al., Obesity Surgery 16, 2006, pp. 773-776.

Alternatively, the total blood volume of the donor (TBV) may becalculated based on the weight (Wt), height (Ht) and sex (Male orFemale) of the donor such that TBV=(0.3669*Ht³)+(0.03219*Wt)+0.6041 forMales and TBV=(0.3561*Ht³)+(0.03308*Wt)+0.1833 for Females, where Ht isin meters and Wt is in kilograms (Nadler's formula).

The percentage by which TBV is multiplied to obtain TVP (and, ultimatelyTVPP) is selected to maximize the volume of pure plasma that iscollected from the donor consistent with donor comfort and safety. Thepercentage ranges in various embodiments may be variously betweenapproximately 1% and 15% of TBV, at least 15%, less than 18%, betweenabout 15% and 17%, about 12%, about 16% or about 18%. The TVPP may alsobe subject to a maximum volume of, e.g., 1000 mL or 1050 mL to becollected regardless of the donor's TBV.

An adjustment, Vc, may be made to the calculated volume of whole bloodTBV before calculating the target volume of pure plasma TVP, such thatTVP=0.36(1−Hct)(TBV−Vc), where Vc=523 mL, based on a regression analysisof the experimental blood volume data presented in Retzlaff et al.,Erythrocyte Volume, Plasma Volume, and Lean Body Mass in Adult Men andWomen, J. Haematology, 33, 5:649-667 (1969). There is a 95% confidencethat an individual's predicted blood volume will differ not more that20.5%. Thus, a scaling factor of 0.795 may be applied to determinationof harvestable raw plasma being 36% of the donor's total plasma volumedescribed above, so that 28.6% of a donor's calculated volume of rawplasma may be harvested, consistent with donor safety and comfort.

Retuning to FIG. 6 b , once the TVPP has been determined, as describedabove (based on the TBV), whole blood is withdrawn from the donor (Step100) and combined with anticoagulant based on a predetermined ratio(Step 102). Anticoagulated whole blood is then introduced into separator14 where it is separated into plasma and concentrated (red blood) cells(Step 104). Plasma product (pure plasma and anticoagulant) is collectedin plasma collection container 28 (Step 106) while separated red bloodcells are collected in reservoir 32. As the plasma product is beingcollected, the volume of plasma product, VPP, (pure plasma andanticoagulant) in the plasma container is determined (Step 108). Whenthe VPP equals the Target volume of plasma product (TVPP), withdrawal ofwhole blood ceases and any remaining blood components (such as red bloodcells) are returned to the donor (Step 110).

Thus, the collection volume (the volume of plasma product) is determinedbased on the volume of raw plasma volume that may be collected from aparticular donor, the donor's hematocrit, and the fixed anticoagulantratio (ACR). Consequently, this methodology allows for more consistentcontrol for the raw plasma volume of the donor, which is the variablemost related to donor safety.

In an exemplary method, the operator enters into the system controllerthe collection volume for the plasma product for the particular donor,based on the target volume of raw plasma that may be harvested. Thetarget plasma collection volume may be as set forth in FIG. 9 , based onthe donor's weight and hematocrit for the initial collection phase, orby any of the other methods as set forth above. Alternatively, thecontroller is configured to calculate the target plasma productcollection volume for the initial collection phase in accordance with amethodology such as those described above upon the operator entering,e.g., the donor's weight and hematocrit, and/or any of the additionaldonor-specific information (such as the donor's sex, height and age)required by the methodologies used for determining a donor's total bloodvolume, total plasma volume, and the target volume of harvestable plasmathat may be collected.

In practice, the operator enters into the system controller thecollection volume for the plasma product for the particular donor, basedon the target volume of raw plasma that may be harvested. The targetplasma collection volume may be as set forth in FIG. 9 , based on thedonor's weight and hematocrit for the initial collection phase, or byany of the other methods as set forth above. Alternatively, thecontroller is configured to calculate the target plasma productcollection volume for the initial collection phase in accordance with amethodology such as those described above upon the operator entering,e.g., the donor's weight and hematocrit, and/or any of the additionaldonor-specific information (such as the donor's sex, height and age)required by the methodologies used for determining a donor's total bloodvolume, total plasma volume, and the target volume of harvestable plasmathat may be collected.

Preferably, the system administrator will initially set an indication ofwhether the targeted collection volume of plasma product, TVPP, will bedetermined by the system (e.g., in accordance with one of the methodsdescribed above) or entered directly by the operator into the system. Ifthe operator is to enter the TVPP, then the system administrator willdisable the controller's capability to calculate a TVPP. The systemadministrator will also set an AC ratio to be used for all procedures.If the controller is to determine the TVPP, the administrator will setthe system to allow the appropriate donor specific characteristics forcalculating the TVPP in accordance with any of the methods describedabove to be entered into the controller, either by the operator or adonor management system, by which donor parameters used forqualification screening (such as weight, height, and hematocrit) can beelectronically sent to the instrument, avoiding operator error inentering the donor parameters. The donor management system could alsoutilize the donor screening measurements, along with the relationshipbetween pure plasma volume and collection volume, to automaticallycalculate a TVPP that it would transmit to the controller of theplasmapheresis device. Otherwise, the controller will calculate the TVPPbefore collection of whole blood form the donor starts. In addition, ifthe controller/donor management system is to calculate TVPP, theadministrator will set the system to enable the operator to enter a TVPPother than the calculated volume. Further, the system will permit theoperator to change the TVPP from the calculated TVPP, either before orduring the procedure, if, for example, the estimated time forrunning/completing the procedure needs to be shortened for reasons ofdonor comfort or convenience. At the completion of the procedure theactual volume of plasma product collected, VPP, and the target volume,TVPP, will be displayed, as well as the actual volume of pure plasmacollected and the target volume of plasma, TPV.

As noted above, plasmapheresis procedures may be performed with multiplecycles of collection/draw phases and return/reinfusion phases. If thereturn/reinfusion phase does not include reinfusion of a replacementfluid, the donor's hematocrit will increase from one cycle to the next.Consequently, if the target volume for plasma product is determinedbased only on the donor's initial hematocrit, and does not consider thedonor's increasing hematocrit, the percentage of anticoagulant in theplasma product will be greater (and the volume of pure plasma less) thanwhat was predicted by the initial calculation for determining the targetvolume of plasma product. Thus, in order to ensure that the volume ofplasma product that is collected contains the maximum volume of rawplasma that was determined to be harvested from a particular donor, thetarget volume for plasma product is recalculated periodically throughoutthe plasmapheresis procedure, such as before the start of the collectionphase of each cycle, to consider the change in the donor's hematocrit.

Accordingly, after the determination of the target volume for plasmaproduct based on the donor's starting hematocrit is made, theplasmapheresis procedure commences with a first draw phase until aspecified volume of whole blood (e.g., approximately 500 ml) has beenwithdrawn from the donor. Anticoagulant is added to the whole blood andthe anticoagulated whole blood is separated into a plasma product, redblood cells, and other non-RBC blood components. At the conclusion ofthe first draw phase, the red blood cells and non-RBC blood componentsare returned to the donor. The current volume of plasma productcollected after the first draw phase is determined by, e.g., the weighscale. Then a current value for the hematocrit of the donor isestablished and a new target volume of plasma product to be collected isdetermined, and the second cycle of draw and return phases is performed.The cycle of draw and return phases is repeated until the target volumeof plasma product tor the plasmapheresis procedure is collected, asrecalculated prior to the start of each draw phase. After the finalcollection phase, the controller initiates the final red blood cellreinfusion stage, after which the donor is disconnected.

The benefits of performing a plasmapheresis procedure having multiplecollection/reinfusion cycles in accordance with the methodology setforth above may be seen by reference to the tables of FIGS. 10 and 11 a,11 b. FIG. 10 displays the input data for a hypothetical plasmapheresisprocedure for a donor weighing 190 lbs. (86.4 kg) and having an initialhematocrit of 44. With reference to the table of FIG. 1 , the simplifiedFDA nomogram would limit the volume of plasma to be collected from sucha donor to 800 mL, and the total collection volume for the plasmaproduct to 880 mL. In the present example, the FDA nomogram limit on thevolume of raw plasma that may be collected is for illustrative purposesonly. As set forth above, other methodologies may be used to determinethe amount of raw plasma that may be safely extracted from a donor thatwould differ from that indicated by the FDA nomogram.

The number of collection and reinfusion cycles in a plasmapheresisprocedure may vary from three to twelve. In the hypotheticalplasmapheresis procedure, there are five collection and reinfusioncycles, which are chosen for illustrative purposes.

Before the commencement of the first collection cycle, the volume of rawplasma to be collected and the total target volume of plasma product tobe collected are determined in accordance with the methodologiesdescribed above, based on the donor's initial hematocrit. As set forthin the first row of the table (Cycle 1 start), the initial target volumefor the plasma product to be collected is 889 mL, which is the same asindicated by the table of FIG. 9 for a donor having a weight of 175 lbs.and up and a hematocrit of 44 in order to harvest the FDA limit of 800mL of raw plasma from the donor.

During each collection phase, 500 mL of whole blood is drawn from thedonor, to which anticoagulant is added at a predetermined ratio (i.e.,1:16), such that 31 mL is added for each collection cycle of 500 mL. Thewhole blood plus anticoagulant is separated into a plasma fraction and ared blood cell fraction.

During the first return phase (Cycle 1 return end), the red blood cellsand “non-RBC” blood components are returned to the donor, so that at theend of the first return cycle the donor's hematocrit has increased to45.6%, as calculated by the controller based on a blood volume beingdecreased by the amount of raw plasma collected, while the quantity ofred blood cells in the total blood volume remains the same as at thestart of the procedure. The controller can also account for the volumeof anticoagulant that is reinfused in each return phase along with thered blood cells, as well as the residual anticoagulant in the donor'swhole blood being drawn in cycles 2 and following, when determining thenew hematocrit value for the next cycle. The volume of raw plasma andthe total target volume of plasma product to be collected for theprocedure are then recalculated based on the donor's new, increasedhematocrit and raw plasma volume. This provides for a new total targetcollection volume of 891 mL.

The second collection phase is then performed, resulting in a total of430 mL of plasma product comprising 386 mL of raw plasma being collectedover the first two collection phases (Cycle 2 draw end). The red bloodcells and “non-RBC” blood components are again returned to the donor,after which the donor's hematocrit is calculated to be 47.2%.

Two more collection phases of 500 mL are performed, each followed by areturn phase, in which new values for the volume of raw plasma and totalvolume of plasma product to be collected are determined before the startof each collection phase. With the increasing hematocrit of the donor,the recalculated target collection volume for procedure increases to 893mL (for the third collection phase) and then to 894 ml (for the fourthcollection phase). A fifth “mini” collection cycle is performed to bringthe volume of raw plasma collected up to the 800 mL permitted by the FDAnomogram for the hypothetical donor. The recalculated target collectionvolume of plasma product for the fifth collection phase remains at 894mL.

Thus, as illustrated in the example above, when the target collectionvolume for the plasma product is recalculated for each collection phase,a target collection volume for the plasma product of 894 mL is obtained,which is required in order to collect the target volume of raw plasma of800 mL. In contrast, 889 mL of plasma product would have been collectedif the target collection volume is determined based only on the donor'sinitial hematocrit, or 880 mL if the target collection volume is basedon the simplified FDA nomogram. In both cases, less than the targetvolume of 800 mL would have been collected.

The greater the accuracy with which the hematocrit of the donor can bedetermined, both before and during the procedure, the more likely thetarget volume of plasma product collected will include the maximumvolume of raw plasma that can be collected for a particular donor. Asdescribed above, the hematocrit of the donor during the procedure isbased on the assumptions that 100% of the red blood cells that arewithdrawn in each draw cycle are reinfused in each return cycle, alongwith 100% of the non-RBC cellular products and a volume ofanticoagulant. However, it has been determined that during the course ofa blood separation procedure, interstitial fluid can shift to theintravascular space, resulting in restoring half of the withdrawnvolume. See, Saito et al., Interstitial fluid shifts to plasmacompartment during blood donation, Transfusion 2013; 53(11):2744-50. Theshifted interstitial fluid is in addition to the red blood cells,non-RBC cellular products, and anticoagulant that are reinfused in eachreturn phase. Thus, accounting for the shift of interstitial fluid wouldresult in a more accurate hematocrit determination, and thus a moreaccurate determination of the target volume for plasma product that willresult in the maximum amount of raw plasma.

The shift of interstitial fluid during plasmapheresis has beensubstantiated by tracking the level of Immunoglobulin G (IgG) of a donorover the course of a plasmapheresis procedure. See, e.g., Burkhardt etal., Immunoglobulin G levels during collection of large volume plasmafor fractionation; Transfusion 2017; 56:417-420. If there were noshifting of interstitial fluid, the IgG level of the donor would bestable over the course of the plasmapheresis procedure. However, the IgGlevel has been shown to drop, and the amount that the IgG level drops isa function of the volume of interstitial fluid that has shifted to theblood system.

With reference to FIG. 12 , a plot of volume of plasma collected (alongthe X-axis versus IgG concentration (along the Y-axis) that wasdeveloped empirically is shown. A 9% drop of the donor's IgG is seenfrom the baseline of zero plasma collected (at the start of theprocedure) to 200 mL of plasma collected, and a drop of an additional 4%from 200 mL to 800 mL collected. This was attributable to a shift ofinterstitial fluid equal to approximately 9% of the donor's initialtotal blood volume (after 200 mL of plasma being collected) toapproximately 13% of the donor's initial total blood volume (after 800mL of plasma being collected).

The following relationship between the amount that the donor's IgGconcentration and the volume of plasma collected has been established:y=1.0017x^(−0.02), where y=IgG concentration and x=plasma volumecollected. Thus, the percentage of the donor's blood volume that isreplaced by the shift of interstitial fluid is equal to V_(b)(1−y),where V_(b) is the donor's initial volume of whole blood. Thus, theshifted volume of interstitial fluid can be calculated based on thevolume of plasma collected, and this amount can be added to the volumeof red blood cells, non-RBC cellular products and anticoagulantreinfused in each return phase to determine the current total bloodvolume, and thus hematocrit, of the donor. As can be appreciated, thecontroller can be configured to automatically determine the volume ofinterstitial fluid that has shifted based on the volume of plasmacollected, and to include the shifted volume when determining thedonor's hematocrit prior to each draw phase.

Alternatively, other methods that directly measure the donor'shematocrit may be employed, such as an optical sensor or, if acentrifugal separator is being used, measuring the volume of red bloodcells in the centrifuge.

In addition, anticoagulant may be introduced into the disposable kitprior to the commencement of the plasmapheresis procedure inpre-processing steps, such as for priming the disposable kit, performingone or more pre-cycles, or for performing other pre-procedure steps. Tothe extent that anticoagulant used for these purposes is ultimatelydirected to the plasma product collection container, it may be accountedfor in determining the volume contained in the plasma collectioncontainer that results in the target volume of raw plasma beingcollected. This may be done, for example, by measuring the weight of the“full” container of anticoagulant and the weight of the container ofanticoagulant prior to the commencement of the first draw cycle, andadding that volume of anticoagulant to the target volume of plasmaproduct. The controller can be configured to automatically perform thesteps necessary to account for the anticoagulant introduced into theplasma collection container separately from the anticoagulated plasma.

The methods and system set forth above have several aspects. In a firstaspect, a method for collecting plasma in which plasma product iscollected in multiple collection phases between which separated redblood cells are reinfused to the donor is provided. The method of thisfirst aspect comprises a) determining a volume of whole blood (V_(b))and hematocrit (Hct) for a donor; b) determining a volume of raw plasma(V_(RP)) that may be collected from the donor; c) determining a volumeof plasma product (V_(PP)) that may be collected, wherein the plasmaproduct comprises the raw plasma volume plus a volume of anticoagulant;d) withdrawing whole blood from the donor; e) introducing anticoagulantinto the withdrawn whole blood at a specified ratio (ACR); f) separatingthe withdrawn whole blood into a plasma product and a second componentcomprising red blood cells; g) collecting the plasma product in a plasmacollection container; h) after a desired amount of whole blood has beenwithdrawn from the donor, returning the red blood cells to the donor;and i) determining the Hct of the donor and V_(PP) prior to eachcollection phase.

In a second aspect, steps d)-i) are continued until a measured volume ofplasma product in the collection container equals V_(PP).

In a third aspect, a method for collecting plasma in which plasmaproduct is collected in multiple collection phases between whichseparated red blood cells are reinfused to the donor is provided. Themethod of this second aspect comprises: a) determining a volume of wholeblood (V_(b)) and hematocrit (Hct) for a donor; b) determining a volumeof raw plasma (V_(RP)) that may be collected from the donor based onV_(b); c) determining a volume of anticoagulant V_(AC) to be added tothe V_(RP) based on an anticoagulant ratio (ACR) and the Hct of thedonor, such that V_(AC)=V_(RP)*(ACR*(1−Hct)); d) determining a volume ofplasma product (V_(PP)) that may be collected, wherein the plasmaproduct comprises the raw plasma volume (V_(RP)) plus the volume ofanticoagulant (V_(AC)); e) withdrawing whole blood from the donor; f)introducing anticoagulant into the withdrawn whole blood at thespecified ratio (ACR); g) separating the withdrawn whole blood into aplasma product and a second component comprising red blood cells; h)collecting the plasma product in a plasma collection container; i) aftera desired amount of whole blood has been withdrawn from the donor,returning the red blood cells to the donor; and j) determining the Hctof the donor and V_(PP) prior to each collection phase.

In a fourth aspect, steps d)-j) are continued until a measured volume ofplasma product in the collection container equals V_(PP).

In a fifth aspect, V_(b) is determined based on one or more donorspecific characteristics including a donor's weight, height, sex, age,and morphology.

In a sixth aspect, a method is provided for collecting a volume ofplasma product (V_(PP)) in an apheresis procedure in which plasmaproduct is collected in multiple collection phases between whichseparated red blood cells are reinfused to the donor. In the method ofthis fourth aspect, V_(PP) is equal to a volume of raw plasma (V_(RP))that may be collected from a donor plus a volume of anticoagulant(V_(AC)) that is added to the V_(RP) during the apheresis procedure. Thesteps of the method comprise: a) determining a weight (W_(kg)) and sex(M or F) for the donor; b) determining a hematocrit (Hct) for the donor;c) determining the volume of raw plasma (V_(RP)) that may be collectedbased on the weight (W_(kg)) and sex (M or F) of the donor; d)determining a ratio K between the V_(PP) and the V_(RP), such thatK=V_(PP)/V_(RP), based on an anticoagulant ratio and the Hct of thedonor; e) determining V_(PP), such that V_(PP)=V_(RP)*K; f) withdrawingwhole blood from the donor; g) introducing anticoagulant into thewithdrawn whole blood at a specified ratio (ACR); h) separating thewithdrawn whole blood into a plasma product and a second componentcomprising red blood cells; i) collecting the plasma product in a plasmacollection container; j) after a desired amount of whole blood has beenwithdrawn from the donor, returning the red blood cells to the donor;and k) determining the Hct of the donor and the target V_(PP) prior toeach collection phase.

In a seventh aspect, steps c)-k) are repeated until a measured volume ofplasma product in the collection container equals V_(PP). Preferably,K=V_(PP)/V_(RP)=(ACR*(1−Hct/100)+1)/(ACR*(1−HCT/100)).

In an eighth aspect, a method is provided for collecting a volume ofplasma product (V_(PP)) in an apheresis procedure in which plasmaproduct is collected in multiple collection phases between whichseparated red blood cells are reinfused to the donor. In this fifthaspect V_(PP) is equal to a volume of raw plasma (V_(RP)) that may becollected from a donor plus a volume of anticoagulant (V_(AC)) that isadded to the V_(RP) during the apheresis procedure. The steps of themethod comprise: a) determining a weight (Wo) and sex (M or F) for thedonor; b) determining a hematocrit (Hct) for the donor; c) determiningthe volume of raw plasma (V_(RP)) that may be collected based on theweight of the donor (W_(kg)) and the sex (M or F) of the donor; d)determining the V_(AC) to be added to the V_(RP) based on ananticoagulant ratio (ACR) and the Hct of the donor, such thatV_(AC)=V_(RP)*(ACR*(1−Hct)); e) determining V_(PP), such thatV_(PP)=V_(RP)+V_(AC); f) withdrawing whole blood from the donor; g)introducing anticoagulant into the withdrawn whole blood at a specifiedratio (ACR); h) separating the withdrawn whole blood into a plasmaproduct and a second component comprising red blood cells; i) collectingthe plasma product in a plasma collection container; j) after a desiredamount of whole blood has been withdrawn from the donor, returning thered blood cells to the donor; and k) determining the Hct of the donorand V_(PP) prior to each collection phase.

In a ninth aspect, steps d)-k) are continued until a measured volume ofplasma product in the collection container equals V_(PP).

In a tenth aspect, V_(RP) is determined by establishing the V_(RP) foreach of a plurality of ranges of donor weight, and selecting the V_(RP)for the range of weight that is inclusive of the weight of the donor.The ranges of donor weight may be in three categories from 110 to 149lbs., 150 to 174 lbs., and 175 lbs. and up.

In an eleventh aspect, V_(RP)=K₁*W_(kg).

In a twelfth aspect, V_(RP) is no greater than 28.6% of (1−Hct)*(V_(b)).

In a thirteenth aspect, V_(b) is determined using one of Nadler'sequations, Gilcher's Rule of Five, the standards of the ICSH, and anyother generally accepted methodology.

In a fourteenth aspect, V_(RP)=W_(kg)*10 mL/kg.

In a fifteenth aspect, when donor parameters are used to estimate atotal blood volume (V_(b)) for the donor, V_(RP)=K₂*V_(b).

In a sixteenth aspect, an automated system for separating plasma fromwhole blood is provided comprising a reusable hardware component and adisposable kit. The disposable kit further comprises i) a separator forseparating whole blood into a plasma fraction and a concentrated cellfraction, the separator having an input having a blood line integrallyconnected thereto for transporting whole blood from a donor to theseparator, a plasma output port integrally connected to a plasmacollection container by a plasma line, and a concentrated cell outletport integrally connected to a reservoir for receipt of concentratedcells prior to reinfusion to the donor; ii) a donor line terminating ina venipuncture needle for transporting whole blood from a donor to theblood line, iii) an anticoagulant line integrally connected to the bloodline and configured to be connected to a source of anticoagulant fortransporting anticoagulant to the donor line, iv) a saline lineconfigured to be attached to a source of saline for transporting salineto the blood line, and v) a reinfusion line for transportingconcentrated cells from the reservoir to the donor line. The reusablehardware component further comprises i) a first peristaltic pump fordelivering anticoagulant at a controlled rate into the blood line duringa collection phase, ii) a second pump for delivering anticoagulatedwhole blood to the separator during the collection phase and forreturning concentrated cellular components during a reinfusion phase,iii) a third pump for delivering concentrated cellular components fromthe separator to the reservoir during the collection phase, iv) a clampassociated with each of the blood line, plasma line, reinfusion line andsaline line, v) a weigh scale for weighing each of the plasma collectioncontainer, the reservoir and the source of anticoagulant, and vi) aprogrammable controller comprising a touch screen for receiving inputfrom an operator, the programmable controller configured to receive asignal from each of the weigh scales and to automatically operate thefirst, second and third pumps and the clamps to separate whole bloodinto a plasma fraction and a concentrated cell fraction during thecollection phase and to return concentrated cells to the donor duringthe reinfusion stage. The programmable controller is further configuredto determine the weight of the plasma fraction to be collected in theplasma collection container in accordance with any of the aspectsdescribed herein, and to terminate the collection phase upon receiving asignal from the weigh scale for the plasma collection container equal tothe weight of the plasma fraction determined by the controller. Indetermining the target amount for the plasma product to be collected,the controller may be configured to calculate the hematocrit of thedonor prior to the collection phase of each cycle. Alternatively, oradditionally, the controller may receive a signal from a sensor or thelike that is indicative of the donor's hematocrit. Further, the amountof plasma product in the plasma collection container may be determinedby, e.g., the weigh scale associated with the plasma collection. In oneembodiment, the separator comprises a spinning membrane separator.

It will be understood that the embodiments described are illustrative ofsome of the applications of the principles of the present subjectmatter. Numerous modifications may be made by those skilled in the artwithout departing from the spirit and scope of the claimed subjectmatter, including those combinations of features that are individuallydisclosed or claimed herein. For these reasons, the scope of the claimsis not limited to the above-description, but is set forth in thefollowing claims.

1. A system for collecting plasma from a donor comprising: a) avenipuncture needle for withdrawing whole blood from the donor; b) ablood separator for separating the whole blood into a plasma; productand a second blood component comprising red blood cells; c) a donor linecoupled to the venipuncture needle for introducing whole blood from thedonor to the blood separator; d) a first pump for controlling flowthrough the donor line; e) an anticoagulant line coupled to ananticoagulant source for combining anticoagulant with the whole blood;f) a second pump for controlling flow through the anticoagulant line; g)a touchscreen is provided for receiving input from an operator; and h) aprogrammable controller configured to: determine a target volume ofplasma product to be collected (TVPP) based on a weight of the donor, orbased on a weight and height of the donor, and a percentage ofanticoagulant in the target volume of plasma product to be collected (%AC_(TVPP)) based on a pre-determined anticoagulant ratio (ACR) and ahematocrit (Hct) of the donor, control the system to operate a draw andreturn cycle to withdraw whole blood from the donor, add anticoagulantto the whole blood at a pre-determined ratio (ACR), separate theanticoagulated whole blood into the plasma product and the secondcomponent and to return the second component to the donor, and stopwithdrawing whole blood from the donor and initiate a final return ofthe second blood component when a measured volume of plasma product in aplasma collection container reaches the target volume for plasmaproduct, TVPP.
 2. The system of claim 1, wherein the controller isfurther programmed to calculate i) a target volume of pure plasmaproduct to be collected (TVP) from the weight of the donor and ii) thepercentage of anticoagulant in the target volume of plasma product to becollected, % AC_(TVPP), based on the pre-determined anticoagulant ratio,ACR, and the hematocrit, Hct, of the donor, wherein the TVPP=TVP/(1−%AC_(TVPP)).
 3. The system of claim 2, wherein the controller is furtherprogrammed to calculate the target volume of pure plasma to becollected, TVP, as a multiple of the weight of the donor.
 4. The systemof claim 1, wherein the controller is further programmed to calculate atotal blood volume of the donor (TBV) based on the weight and height ofthe donor, a target volume of pure plasma product to be collected, TVP,as a percentage of the TBV, and the percentage of anticoagulant in thetarget volume of plasma product to be collected, % AC_(TVPP), based onthe pre-determined anticoagulant ratio, ACR, and the hematocrit, Hct, ofthe donor, wherein the TVPP=TVP/(1−% AC_(TVPP)).
 5. The system of claim4, wherein the controller is further programmed to calculate the totalblood volume of the donor, TBV, based on the weight and height of thedonor to calculate a body mass index for the donor (BMI) such thatTBV=70/sqrt(BMI/22), where BMI=Wt/Ht².
 6. The system of claim 1, whereinACR is the ratio of the amount of whole blood to the amount ofanticoagulant (ACR=WB/AC), and the controller is further configured todetermine the percent of anticoagulant in the target volume of plasmaproduct, % AC_(TVPP), such that % AC_(TVPP), =1/(1+ACR(1−Hct)).
 7. Thesystem of claim 1, wherein ACR is the ratio of volume of whole bloodplus the volume of anticoagulant to the volume of anticoagulant(ACR=(WB+AC)/AC), and the controller is further configured to determinethe percent of anticoagulant in the target volume of plasma product, %AC_(TVPP), such that % AC_(TVPP)=1/(1+(ACR−1)(1−Hct)).
 8. The system ofclaim 4, wherein the controller is further programmed to calculate thetotal blood volume of the donor (TBV) based on the weight (Wt), height(Ht) and sex (Male or Female) of the donor such thatTBV=(0.3669*Ht³)+(0.03219 Wt)+0.6041 for Males andTBV=(0.3561*Ht³)+(0.03308*Wt)+0.1833 for Females, where Ht is in metersand Wt is in kilograms.
 9. A method for collecting a target volume ofplasma product (TVPP) from a donor, wherein TVPP comprises a targetvolume of pure plasma (TVP) plus a volume of anticoagulant, comprising:a) determining TVPP by first calculating the target volume of pureplasma to be collected from the donor, TVP, as a multiple of the weightof the donor, and determining a percentage of anticoagulant in the TVPP,(% AC_(TVPP)), such that TVPP=TVP/(1−% AC_(TVPP)), wherein % AC_(TVPP)is based on an anticoagulant ratio (ACR) and a hematocrit (Hct) of thedonor; b) withdrawing whole blood from the donor; c) mixinganticoagulant with the whole blood at the anticoagulant ratio, ACR; d)separating the anticoagulated whole blooded into plasma product, redblood cells, and other cellular components; e) collecting the plasmaproduct in a container; f) determining a volume of plasma product in thecontainer, VPP; and g) when VPP=TVPP, ceasing withdrawal of whole bloodfrom the donor and returning the red blood cells and other cellularcomponents to the donor.
 10. The method of claim 9, further comprisingdetermining the percent of anticoagulant in the target volume of plasmaproduct, % ACT PP, such that % AC_(TVPP)=1/(1+ACR(1−Hct)), wherein ACRis the ratio of the amount of whole blood to the amount of anticoagulant(ACR=WB/AC).
 11. The method of claim 9, further comprising determiningthe percent of anticoagulant in the target volume of plasma product, %AC_(TVPP), such that % AC_(TVPP)=1/(1+(ACR−1)(1−Hct)), wherein ACR isthe ratio of volume of whole blood plus the volume of anticoagulant tothe volume of anticoagulant (ACR=(WB+AC)/AC).
 12. The method of claim 9,further comprising collecting the target volume of pure plasma, TVPP, ina plurality of cycles, each cycle comprising a collection phase in whichwhole blood is withdrawn from the donor and a return phase in which thered blood cells and other cellular components are returned to the donor;determining the hematocrit, Hct, of the donor prior to the collectionphase of each cycle, and recalculating the target amount for the plasmaproduct to be collected TVPP based on the hematocrit, Hct, of the donorthat is determined prior to the collection phase of each cycle.
 13. Amethod for collecting a target volume of plasma product (TVPP) from adonor, wherein TVPP comprises a target volume of pure plasma TVP plus avolume of anticoagulant, comprising: a) determining TVPP by firstcalculating a total blood volume (TBV) for the donor based on a weightand height of the donor, calculating a target volume of pure plasma(TVP) to be collected from the donor as a percentage of the TBV, anddetermining a percentage of anticoagulant in the TVPP, % AC_(TVPP), suchthat TVPP=TVP/(1−% AC_(TVPP)), wherein % AC_(TVPP) is based on ananticoagulant ratio (ACR) and a hematocrit (Hct) of the donor; b)withdrawing whole blood from the donor, c) mixing anticoagulant with thewhole blood at the anticoagulant ratio, ACR; d) separating theanticoagulated whole blooded into plasma product, red blood cells, andother cellular components; e) collecting the plasma product in acontainer; f) determining a volume of plasma product in the container,(VPP); and g) when VPP=TVPP, ceasing withdrawal of whole blood from thedonor and returning the red blood cells and other cellular components tothe donor.
 14. The method of claim 13, further comprising determiningthe percent of anticoagulant in the target volume of plasma product, %AC_(TVPP), such that % AC_(TVPP)=1/(1+ACR(1−Hct)), wherein ACR is theratio of the amount of whole blood to the amount of anticoagulant(ACR=WB/AC).
 15. The method of claim 13, further comprising determiningthe percent of anticoagulant in the target volume of plasma product, %AC_(TVPP), such that % AC_(TVPP)=1/(1+(ACR−1)(1−Hct)), wherein ACR isthe ratio of volume of whole blood plus the volume of anticoagulant tothe volume of anticoagulant (ACR=(WB+AC)/AC).